OBJECTIVE: Endothelium is an important target for gene therapy. We have investigated the effect of viral and nonviral vectors on the phenotype and function of endothelial cells (ECs) and developed methods to block any activation caused by these vectors. METHODS AND RESULTS: Transduction of ECs with viral vectors, including adenovirus, lentiviruses, and Moloney murine leukemia virus, can induce a pro-inflammatory phenotype. This activation was reduced when nonviral vectors were used. We demonstrate that after transduction there is upregulation of dsRNA-triggered antiviral and PI3K/Akt signaling pathway. Blockade of the NFkappaB, PI3-K, or PKR signaling pathways all operated to inhibit partially virally induced activation, and inhibition of both PKR and PI3-K pathways totally blocked EC activation. Furthermore, inhibition of IFN-alpha/beta in addition to PI3-K was effective at preventing EC activation. CONCLUSIONS: Viral vectors, although efficient at transducing ECs, result in their activation. Blockade of the signaling pathways involved in viral activation may be used to prevent such activation.
OBJECTIVE: Endothelium is an important target for gene therapy. We have investigated the effect of viral and nonviral vectors on the phenotype and function of endothelial cells (ECs) and developed methods to block any activation caused by these vectors. METHODS AND RESULTS: Transduction of ECs with viral vectors, including adenovirus, lentiviruses, and Moloney murine leukemia virus, can induce a pro-inflammatory phenotype. This activation was reduced when nonviral vectors were used. We demonstrate that after transduction there is upregulation of dsRNA-triggered antiviral and PI3K/Akt signaling pathway. Blockade of the NFkappaB, PI3-K, or PKR signaling pathways all operated to inhibit partially virally induced activation, and inhibition of both PKR and PI3-K pathways totally blocked EC activation. Furthermore, inhibition of IFN-alpha/beta in addition to PI3-K was effective at preventing EC activation. CONCLUSIONS: Viral vectors, although efficient at transducing ECs, result in their activation. Blockade of the signaling pathways involved in viral activation may be used to prevent such activation.
Authors: Peng H Tan; Shao-An Xue; Bin Wei; Angelika Holler; Ralf-Holger Voss; Andrew J T George Journal: Mol Med Date: 2007 Mar-Apr Impact factor: 6.354
Authors: Peng H Tan; Helen E J Tyrrell; Liquan Gao; Danmei Xu; Jianchao Quan; Dipender Gill; Lena Rai; Yunchuan Ding; Gareth Plant; Yuan Chen; John Z Xue; Ashok I Handa; Michael J Greenall; Kenneth Walsh; Shao-An Xue Journal: Cancer Res Date: 2014-09-26 Impact factor: 12.701
Authors: Pamela M Rogers; Nazar Mashtalir; Miloni A Rathod; Olga Dubuisson; Zhong Wang; Kumar Dasuri; Scott Babin; Alok Gupta; Nathan Markward; William T Cefalu; Nikhil V Dhurandhar Journal: Diabetes Date: 2008-07-03 Impact factor: 9.461